title: Transgenic rescue of ataxia mice reveals a male-specific sterility defect.
abstract: Homozygous ataxia (ax(J)) mice have reduced expression of ubiquitin-specific protease 14 (Usp14), resulting in severe neuromuscular defects and death by 2 months of age. Transgenic expression of Usp14 exclusively in the nervous system of ax(J) mice (ax(J)-Tg) prevents early lethality and restores motor system function to the ax(J) mice, enabling an analysis of the reproductive capabilities of Usp14-deficient mice. Although female ax(J)-Tg mice had a 75% reduction of Usp14 in the ovaries, they were able to produce normal litters. Ovary transfer experiments also demonstrated that the ovaries of ax(J) mice were capable of producing viable pups. In contrast, male ax(J) and ax(J)-Tg mice displayed a 50% reduction in testicular Usp14 levels and were infertile, indicating that Usp14 is required for development and function of the male reproductive system. Immunohistochemistry experiments showed that Usp14 is found in the redundant nuclear envelope and cytoplasmic droplet of epididymal spermatozoa. Analysis of ax(J) testes demonstrated a 50% reduction in testis weight, a 100-fold reduction in sperm number and the presence of abnormal spermatozoa in the epididymis. Histological examination of the Usp14-deficient testes revealed abnormal spermatogenesis and the presence of degenerating germ cells, indicating that Usp14 and the ubiquitin proteasome system are required for spermatid differentiation during spermiogenesis.
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Crimmins
authors.forename: Miriam
authors.initials: M
authors.lastname: Sutovsky
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Chen
authors.forename: Alexis
authors.initials: A
authors.lastname: Huffman
authors.forename: Crystal
authors.initials: C
authors.lastname: Wheeler
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swing
authors.forename: Kevin
authors.initials: K
authors.lastname: Roth
authors.forename: Julie
authors.initials: J
authors.lastname: Wilson
authors.forename: Peter
authors.initials: P
authors.lastname: Sutovsky
authors.forename: Scott
authors.initials: S
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001259:Ataxia / Q000150:complications* / Q000473:pathology*; D004303:Dosage Compensation, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006579:Heterozygote; D007248:Infertility, Male / Q000150:complications* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D021381:Protein Transport; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000196:embryology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism
chemical_list: C469268:Usp14 protein, mouse; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase